Nitric Oxide Destroys Zinc-Sulfur Clusters Inducing Zinc Release from Metallothionein and Inhibition of the Zinc Finger-Type Yeast Transcription Activator LAC9

Kröncke, Klaus‐Dietrich; Fehsel, Karin; Schmidt, Thorsten; Zenke, Frank T.; Dasting, I.; Wesener, J.R.; Bettermann, H.; Breunig, Karin D.; Kolb-Bachofen, Victoria

doi:10.1006/bbrc.1994.1564

Cited by 277 publications

(203 citation statements)

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“…6). Mobilization of zinc has been shown to reversibly inhibit the transcription factors LAC9, Sp1, and EGR-1 in eukaryotic cells (41,42), and the DNA repair enzymes DNA ligase and O 6 -methylguanine DNA methyltransferase in E. coli (43,44). We therefore propose that zinc metalloproteins involved in DNA replication and the restarting of collapsed replication forks (e.g., PriA, DnaG, DnaJ) might be targeted during nitrosative stress.…”

Section: Discussionmentioning

confidence: 94%

Inhibition of bacterial DNA replication by zinc mobilization during nitrosative stress

Schapiro

Libby

Fang

2003

Proc. Natl. Acad. Sci. U.S.A.

110

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Phagocytic cells inhibit the growth of intracellular pathogens by producing nitric oxide (NO). NO causes cell filamentation, induction of the SOS response, and DNA replication arrest in the Gramnegative bacterium Salmonella enterica. NO also induces doublestranded chromosomal breaks in replication-arrested Salmonella lacking a functional RecBCD exonuclease. This DNA damage depends on actions of additional DNA repair proteins, the RecG helicase, and RuvC endonuclease. Introduction of a recG mutation restores both resistance to NO and the ability of an attenuated recBC mutant Salmonella strain to cause lethal infection in mice, demonstrating that bacterial DNA replication is inhibited during host-pathogen interactions. Inhibition of DNA replication during nitrosative stress is invariably accompanied by zinc mobilization, implicating DNA-binding zinc metalloproteins as critical targets of NO-related antimicrobial activity.

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Section: Discussionmentioning

confidence: 94%

Inhibition of bacterial DNA replication by zinc mobilization during nitrosative stress

Schapiro

Libby

Fang

2003

Proc. Natl. Acad. Sci. U.S.A.

110

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“…Due to the different metal affinities for zinc and cadmium in the two separate domains [13], the b-domain has been implicated in zinc homeostasis and the tight binding of cadmium in the a-domain was proposed to be responsible for the role of MTs in heavy metal detoxification. In addition, it has been reported that MTs act as radical scavengers under oxidative stress [20][21][22].Another possible key player in the role of MTs in signal transduction might be nitric oxide (NO), which was shown recently, both in vitro [23][24][25] and in vivo [26][27][28][29], to interact with MTs and thereby releases bound zinc and cadmium. The importance of MTs in NO-induced changes in intracellular zinc homeostasis has been reported by St Croix et al [30].…”

mentioning

confidence: 99%

“…Another possible key player in the role of MTs in signal transduction might be nitric oxide (NO), which was shown recently, both in vitro [23][24][25] and in vivo [26][27][28][29], to interact with MTs and thereby releases bound zinc and cadmium. The importance of MTs in NO-induced changes in intracellular zinc homeostasis has been reported by St Croix et al [30].…”

mentioning

confidence: 99%

Modulation of nitric oxide‐mediated metal release from metallothionein by the redox state of glutathione in vitro

Khatai

Goessler

Lorencova

et al. 2004

European Journal of Biochemistry

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Metallothioneins (MTs) release bound metals when exposed to nitric oxide. At inflammatory sites, both metallothionein and inducible nitric oxide synthase (iNOS) are induced by the same factors and the zinc released from metallothionein by NO suppresses both the induction and activity of iNOS. In a search for a possible modulatory mechanism of this coexpression of counteracting proteins, we investigated the role of the glutathione redox state in vitro because the oxidation state of thiols is involved in the metal binding in Cd-S or Zn-S clusters found in metallothioneins, and NO also binds to reduced glutathione via S-nitrosation. Using a variety of techniques, we found that NO and also ONOO --mediated metal release from purified MTs is suppressed by reduced glutathione (GSH), but not by oxidized glutathione. Considering the millimolar concentrations of GSH present in mammalian cells, the metal release from MTs by NO should play no role in living systems. Therefore, the fact that it has been observed in vivo points to a hitherto unknown mechanism or additional compound(s) being involved in this physiologically relevant reaction and as long as this additional factor is not found experimental results on the MT-NO interaction should be treated with caution. Contrary to the peroxynitrite-induced activation of guanylyl cyclase, where GSH is needed, we found that the metal release from metallothionein by peroxynitrite is not enhanced, but also suppressed by reduced glutathione. In addition, we show that zinc, the major natural metal ligand in mammalian MTs and suppressor of iNOS, is released more readily under the influence of NO than cadmium, but in contrast to the MT isoform 1, the amount of metal released from the b-domain of MT-2 is comparable to that from the a-domain.Keywords: glutathione; metallothionein; nitric oxide; NMR spectroscopy; SEC-ICPMS.Metallothioneins (MTs) are a family of small (6-7 kDa) metal-binding proteins [1][2][3] with the highest known metal content after ferritins. The high amount of cysteine residues in MTs (30% of all amino acids are cysteine) allows these proteins to coordinate multiple mono (Cu + , Ag + ) or divalent metals (Zn 2+ , Cd 2+ ). Mammalian MTs bind seven divalent metals in two separate domains [4]. Three metals are bound in an M 3 Cys 9 cluster in the N-terminal b-domain, while an M 4 Cys 11 four metal cluster is formed in the C-terminal a-domain [4]. Of the four known mammalian MT isoforms [2], the two best studied and most widely occurring isoforms (1 and 2) are most abundant in parenchymatous tissues, i.e. liver, kidney, pancreas and intestines [5][6][7] . The naturally bound metal zinc can be displaced by cadmium up to about 5 mol per mol protein by simple addition of Cd 2+ [13] in vitro. Living animals fed a cadmium-rich diet produce a mixed-metal MT with zinc bound preferentially in the b-and cadmium in the a-domain [11,13,14]. The artificial Cd 7 -MT can only be obtained after complete zinc removal by lowering the pH [15] in vitro.Although the biological function(s) o...

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“…Kroncke, Kolb-Bachofen and colleagues have shown that NO can nitrosate various zinc dependent transcription factors and modify their contribution to gene expression (84). For example, they originally noted that NO caused the release of zinc from Sp1 and EGR-1 (85) resulting in loss of their DNA binding activity.…”

Section: Nitric Oxide Nitric Oxide S-nitrosation and Zinc Sulfur CLmentioning

confidence: 99%

“…The chemical biology underlying this process as well as other redox sensitive aspects of zinc-sulfur complexes has recently been reviewed (87). Kroncke and colleagues originally showed that NO could S-nitrosate the major intracellular zinc-binding protein, MT (84), and cause the release of zinquin-detectable changes in free zinc (6). The effect appeared to be cell-specific in that NO increased detectable labile zinc in endothelial cells, whereas it reduced this signal in cultured pancreatic islet cells (88).…”

Section: No and Zinc Homeostasismentioning

confidence: 99%

Nitric Oxide and Zinc Homeostasis in Acute Lung Injury

Croix

Leelavaninchkul²,

Watkins³

et al. 2005

Proceedings of the American Thoracic Society

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Among putative small molecules that affect sensitivity to acute lung injury, zinc and nitric oxide are potentially unique by virtue of their interdependence and dual capacities to be cytoprotective or injurious. Nitric oxide and zinc appear to be linked via an intracellular signaling pathway involving S-nitrosation of metallothoineinitself a small protein known to be an important inducible gene product that may modify lung injury. In the present article, we summarize recent efforts using genetic and fluorescence optical imaging techniques to: (1 ) demonstrate that S-nitrosation of metallothionein affects intracellular zinc homeostasis in intact pulmonary endothelial cells; and (2 ) reveal a protective role for this pathway in hyperoxic and LPS-induced injury.

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Nitric Oxide Destroys Zinc-Sulfur Clusters Inducing Zinc Release from Metallothionein and Inhibition of the Zinc Finger-Type Yeast Transcription Activator LAC9

Cited by 277 publications

References 0 publications

Inhibition of bacterial DNA replication by zinc mobilization during nitrosative stress

Inhibition of bacterial DNA replication by zinc mobilization during nitrosative stress

Modulation of nitric oxide‐mediated metal release from metallothionein by the redox state of glutathione in vitro

Nitric Oxide and Zinc Homeostasis in Acute Lung Injury

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